We will capitalize on recent advances in next-generation DNA sequencing to link natural products with the genomes of the microbes that produce them, providing insights into the genetic underpinnings of their synthesis and informing on search strategies for their discovery. Focusing on Global Health: Natural products arguably represent the best drug leads to treat infectious diseases, including those that are the most harmful worldwide. Thus, our work has the potential to lead to drugs relevant to global health. The title of the proposal is: Discovery of natural product-based drugs from bacterial symbionts of insects. Natural products serve as critical drugs or drug precursors with broad pharmaceutical application, including serving as the most effective antibiotics. The wide-spread and rapid evolution of antibiotic-resistance in pathogenic microbes makes the discovery of novel therapeutics to treat infectious diseases of urgent importance. Despite this critical need, small molecule discovery has decreased substantially in recent decades and the pipeline of new antibiotics is rapidly diminishing. The broad goals of this project are to discover novel natural products with high therapeutic potential (Aim 1), identify the anti-infective potential of these small molecules as drug leads through in vitro high throughput screening and murine model work (Aim 2), and, through genomic approaches, to gain insights into the metabolic potential of these bacteria for discovery of secondary metabolites (Aim 3). In our work, we will focus on a large and untapped source of new natural products: insect-associated Actinobacteria. These bacteria appear to be selected by their insect host for their ability to make biologically active small molecules and recent work by Drs. Currie (PI) and Clardy (co-I) has discovered 5 new small molecules, indicating that they represent a promising source for the discovery of natural products. The work proposed by our multidisciplinary team holds the promise to impact the field of drug discovery, generate numerous new drug leads with therapeutic potential and, by translation, to impact the treatment of drug-resistant infectious diseases on a global scale. PUBLIC HEALTH RELEVANCE: Escalating antimicrobial resistance is a major biomedical challenge. We propose discovering novel natural products and evaluating their efficacy as drug leads for treating infectious diseases of significance for US and Global Heath.